Pancreatic cancer is resistant to essentially all standard therapies, which are toxic and generally ineffective as demonstrated by the fact that disease survival has not significantly improved in nearly 50 years. Novel approaches to treatment are therefore urgently needed. This project investigates the role of chimeric antigen receptor (CAR) modified T cell therapy to treat pancreatic cancer. This approach involves isolation of T cells from patients, which are then genetically modified to confer antigen specificiy with tumor-directed chimeric antigen receptors and expanded ex vivo. The transgenic product is then translated to clinical grade and ultimately infused to the patient. This form of treatment has proven both safe and clinically effective for various hematologic and solid malignancies, and we propose investigating the potential of this treatment modality in patients with pancreatic ductal adenocarcinoma (PDAC). However, while our adoptively-transferred effector T cells may be of clinical benefit due their ability to kill antigen-expressing tumor cells, pancreatic cancer is a disease characterized by an immunosuppressive tumor microenvironment, with an infiltrate of Th2- polarized/suppressive cells that produce cytokines, such as IL4, that promote fibrogenesis, support tumor growth, protect cancer cells from apoptosis, and directly inhibit effector T cell function. To overcome this obstacle we will first confer patient-derived T cells with tumor specificity via the expression of a CAR targeting PSCA, a tumor associated antigen that is overexpressed by 70-80% of PDAC cells. Next, we will further engineer these CAR-PSCA T cells to utilize tumor-produced IL4 to instead promote T cell expansion and persistence. This will be accomplished by co-expressing a chimeric cytokine receptor on our CAR T cells that contains the cytokine-binding exodomain of the IL4 receptor chain linked to the signal transducing endodomain of the IL7 receptor. In this way, when engaged with local IL4, our chimeric cytokine receptor (4/7R) will transmit a proinflammatory Th1 signal to our CAR-PSCA T cells, thereby sustaining their cytotoxic activity in vivo. Our central hypotheses are that i) tumo-specific T cells can be prepared from patient peripheral blood via transgenic expression of a CAR targeting PSCA and ii) that these cells will retain their cytotoxic function at the suppressive tumor microenvironment via signaling through our custom 4/7R complex. The completion of this proposal will determine the cytotoxic potential of CAR-PSCA T cells and the efficacy of the 4/7R complex in protecting these cells from tumor-produced suppressive molecules. If successful, data from this study will form the basis for a Phase I clinical study of customized CAR- PSCA 4/7R T cells for the treatment of patients with pancreatic ductal adenocarcinoma.